Cancer is the second leading cause of mortality in the USA and Puerto Rico (PR). Breast cancer (BC) is the most common cancer in women in PR. The DNA repair capacity (DRC) is a critical system aimed at protecting the integrity and stability of the genome. The overall aim of this incident case-control study is to examine whether a low DRC is a predictor of breast cancer and to identify whether the expression of genes that are associated with DNA repair capacity vary as a function of age and subtype of BC. Because age is one of the most important risk factor for cancer and DRC declines with age, this project will identify recently discovered critical genes associated with the loss of DRC. This will be achieved by pursuing the following Specific Aims: 1) to test whether DRC can be utilized as a predictor for BC risk in women of different age groups. Data gathered during the current cycle have shown that women (n=283) in PR with BC have a statistically (p<0.001) significant reduction (56%) in age-adjusted DRC compared to controls (n=479). 2) to identify whether the expression of DNA repair genes that are associated with various phenotypes of DRC vary as a function of age. It is hypothesized that women with BC have an altered expression of key DNA repair genes as a function of age. 3) To study key epidemiological risk factors for breast cancer and their association with DRC in women. 4) To develop scientific expertise in the area of epigenetics and to utilize these newfound tools in cancer studies in the laboratory of the PI. Lymphocytes of women with BC and cancer-free controls will be compared for their DRC using the host-cell reactivation assay with a LUC plasmid. Data will be stratified by DNA repair level and age group. The crude and the multiple logistic regression adjusted odds ratios will be used as measures of association between BC, DRC, and other epidemiological factors, adjusting for all confounders simultaneously. Tumor and normal tissue samples will be evaluated for the differential expression of DNA repair genes. The novel genomic, epigenetic and phenotypic traits associated with BC that will be identified in this study will provide a means to more accurately predict BC risk. PUBLIC HEALTH RELEVANCE: Breast cancer is the number one cancer killer of women in Puerto Rico, and ageing is one of the most important risk factors. The focus of this study is to examine whether a low DNA repair capacity is a predictor of breast cancer and identify whether the expression of genes that are associated with it vary as a function of age. This research includes the study of key genomic, epigenetic and epidemiological risk factors for breast cancer and their association with DNA repair capacity in women. The results are already providing valuable information on which specific DNA repair genes are deregulated and associated with the defects we have found in DNA repair capacity impacting BC progression, and on unique insights into the BC phenotype-genotype relationship. This study will also provide the opportunity to the PI and students to develop scientific expertise in the area of epigenetics to use in future cancer studies. The results of this project will provide information and new methodologies to identify women with high risk of breast cancer and new ways for breast cancer screening.